Abstract: IntroductionAsthma is defined as a chronic inflammatory disorder of the lower airways resulting in an obstruction of airflow, which may be completely or partially reversed with or without specific therapy.The inflammation is an interaction between various cells and cytokines.Asthmatic patients have recurrent or persistent bronchospasm, which causes symptoms e.g.wheezing, breathlessness, chest tightness, and cough, particularly at night or after exercise.Chronic airway inflammation causes bronchial hyperresponsiveness (BHR), which is defined as the inherent tendency of the airways to narrow in response to various stimuli (eg, environmental allergens and irritants). 1 EpidemiologyThe prevalence of childhood asthma is 10 times higher in developed countries (UK, US, Australia and New Zealand) than in developing countries.[4][5][6] Asthma in children accounts for more school absences and more hospitalizations than any other chronic illness and is the most common diagnosis at admission. 7300 million individuals worldwide have asthma.Prevalence of asthma is increasing, especially in children.WHO has estimated that 15 million disability-adjusted life-years are lost and 250,000 asthma deaths are reported worldwide. 8 PathophysiologyThe interplay between environment and genetic factors lead to airway inflammation, which result in functional and structural changes in the airways in the form of bronchospasm, mucosal edema, and mucus plugs, which increases resistance to airflow and decreases expiratory flow rates.Although over-distention helps maintain airway patency, and improves expiratory flow; it also alters pulmonary mechanics and increases the work of breathing, resulting ultimately in alveolar hypoventilation. 9[12][13] www.intechopen.comBronchial Asthma -Emerging Therapeutic Strategies 150 Patients with acute asthma exacerbations in the early stages, have hypoxemia in the absence of carbon dioxide retention, as increases in alveolar ventilation prevents hypercarbia. 14 obstruction continues and ventilation-perfusion mismatch worsens, carbon dioxide retention and respiratory alkalosis occur.Later, the increased work of breathing, increased oxygen consumption, and increased cardiac output lead to metabolic acidosis. Inflammation of the airwaysThe inflammatory process in the airways causes increased BHR, which leads to bronchospasm and typical symptoms of wheezing, shortness of breath, and coughing after exposure to allergens, environmental irritants, viruses such as RSV, Rhinovirus a.o., cold air, or exercise. 17Lymphocytes play a central role in the pathogenesis of asthma.Airway inflammation may represent a mis-balance between two "opposing" populations of T helper (Th) lymphocytes.Two types of Th lymphocytes have been characterized: Th1 and Th2.Th1 cells produce interleukin (IL)-2 and interferon-a (IFN-a), which are critical in cellular defense mechanisms in response to infection.[20][21][22] Cytokines play a key role in orchestrating the chronic inflammation of asthma and other obstructive airways disease recruiting, activating, and promoting the survival of multiple inflammatory cells in the respiratory tract.Cytokines are classified into lymphokines (cytokines that are secreted by T cells and regulate immune responses), proinflammatory cytokines (cytokines that amplify and perpetuate the inflammatory process), growth factors (cytokines that promote cell survival and result in structural changes in the airways), chemokines (cytokines that negatively modulate the inflammatory response).23Epithelial cells in the airways play an important role in orchestrating the inflammation of asthma through the release of multiple cytokines.Th2 cells orchestrate the inflammatory response in asthma through the release of IL-4 and IL-13 (which stimulate B cells to synthesize IgE), IL-5 (which is necessary for eosinophilic inflammation), and IL-9 (which stimulates mast cell proliferation).Mast celles are thus orchestrated by several interacting cytokines and play an important role in asthma through the release of the bronchoconstrictor mediator histamine, cysteinyl-leukotrienes (Cys-LTs), and PGD2) Bronchial biopsies from asthmatics show infiltration with eosinophils, activated mast cells, and T cells that are predominantly Th2 cells.There are characteristic structural changes, with collagen deposition under the epithelium (also described as basement membrane thickening) and increased airway smooth muscle as a result of hyperplasia hypertrophy.There is also an increase in the number of blood vessels angiogenesis) as well as mucus hyperplasia.24In patients with asthma, there is an increase in the number of CD4+ Th cells in the airways, which are predominantly of the Th2 subtype.Th2 cells are characterized by secretion of IL-4, IL-5, IL-9, and IL-13.The transcription factor GATA-binding protein 3(GATA3) is crucial for the differentiation of uncommitted naïve T cells into Th2 cells and regulates the secretion of Th2 cytokines.There is an increase in the number of GATA3+ T cells in the airways of stable asthmatic subjects.Nuclear factor of activated Tcells (NFAT) is a T-cell-specific transcription factor and enhances the transcriptional activation of the IL4 promoter by GATA3.Finally, IL-33, a member of the IL-1 family of cytokines, promotes differentiation of Th2 cells by translocating to the nucleus and regulating transcription through an effect on chromatin structure, but it also acts as a selective chemoattractant of Th2 cells.25 IL-4 plays a critical role in differentiation of Th2 cells from uncommitted Th0 cells and may be important in initial sensitization to allergens.It is also important for isotype switching of B cells from producers of IgG to producers of IgE.IL-12 mimics IL-4 in inducing IgE secretion and causing structural changes in the airways but does not play a role in promoting Th2 cell differentiation.IL-5 plays a key role in inflammation mediated by eosinophils, since it is critically involved in the differentiation of eosinophils from bone marrow precursor cells and also prolongs eosinophils survival.Systemic and local administration of IL-5 to asthmatic patients results in an increase in circulating eosinophils and CD34+ eosinophil precursors.The transcription factor T-bet is crucial for the Th1 cell differentiation and secretion of the Th1-type cytokine IFN-.Consistent with the prominent role of Th2 cells in asthma, T-bet expression is reduced in T cells from the airways of asthmatic patients compared with airway T cells from nonasthmatic patients. www.intechopen.com Management of Asthma in Children 151In recent years more focus on "the hygiene hypothesis", which is in a simplified way, a cytokine imbalance resulting in a dramatic increase in asthma prevalence in Westernized countries.This hypothesis is based on the concept that the immune system of the newborn is skewed toward Th2 cytokine generation (mediators of allergic inflammation).[30] Type 1 IFNs (IFN-and IFN-) and type III IFNs (IFN-) play an important role in innate immunity against viral infections, but IFN-and IFN-show reduced expression in epithelial cells of asthmatic patients and are associated with increased rhinovirus replication, which may predispose these patients to viral exacerbations of asthma.IL-12 plays an important role in differentiating the activating Th1 cells and is produced by activated macrophages, DCs, and airway epithelial cells.IL-12 induces T cells to release IFN-, which regulates the expression of IL-12R 2 and so maintains the differentiation of Th1 cells, whereas IL-4 suppresses IL-12R 2 expression and thus antagonizes Th1 cell differentiation.26Thymic stromal lymphopoietin.Thymic stromal lymphopoietin (TSLP) is a cytokine belonging to the IL-7 family that shows a marked increase in expression in airway epithelium and mast cells of asthmatic patients.TSLP is released from airway epithelial cells, and its synergistic interaction with IL-1 and TNF-results in the release of Th2 cytokines from mast cells independently of T cells.TSLP also plays a key role in programming airway DCs to release the Th2 chemoattractants CCL17 and CCL2 and thus is important in recruiting Th2 cells to the airways.GM-CSF plays role in the differentiation and survival of neutrophils, eosinophils, and macrophages and has been implicated in asthma.Its receptor comprises and -chain that is specific for the receptor for GM-CSF and achain that is also part of the receptors for IL-3 and IL-5.GM-CSF is secreted predominantly by macrophages, epithelial cells, and T cells in response to inflammatory stimuli.Airway epithelial cells of asthmatic patients strongly express GM-CSF, which may condition DCs to direct Th2 immunity and to prolong the survival of eosinophils.27Neutrophins are cytokines that play an important role in the function, proliferation, and survival of autonomic nerves.In sensory nerves, neutrophins increase responsiveness and expression of tachykinins.Nerve growth factor (NGF) may be produced by mast cells, lymphocytes, macrophages, and eosinophils as well as structural cells, such as epithelial cells, fibroblasts, and airwy smooth muscle cells. 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